COMPUTATIONAL MODELING OF ION TRANSPORT AND ENERGY DEPLETION AT VESTIBULAR SYNAPSES: RELEVANCE TO ALZHEIMER?S DISEASE Project Summary In our parent award, ?Synaptic Processing in the Vestibular System,? our goal is to develop computational models of how the distribution of ion channels and transporters contributes to afferent firing at the type I vestibular hair cell synapse. Specifically, we are investigating the roles of quantal and non-quantal transmission at this unique synapse. Recent research from various types of studies indicates links between the proper function of the vestibular system and Alzheimer's disease. Of particular interest is research that suggests that falls precede detectable cognitive changes in Alzheimer's patients. Such studies point to the possibility that changes at the vestibular periphery could be an early and undetectable event that disrupts normal synaptic transmission. As the vestibular afferents project to the hippocampus, it is reasonable to hypothesize that reduced synaptic input may contribute to the development of Alzheimer's and other neurodegenerative diseases. This hypothesis forms the fundamental motivation for this supplement proposal. Indeed, much research indicates that Alzheimer's disease is linked to energetic depletion, aberrant functions of ion channels, and disorders of ion homeostasis. Here we propose to extend our current biophysical model of the vestibular-hair cell calyx synapse n several ways, including through the inclusion of a more complete model of the Na/K pump that permits us to model energetic depletion and through the inclusion of recent data on membrane transporter and ion channel changes associated with Alzheimer's disease. This effort will increase our understanding of the vestibular periphery within the scope of the original grant, and also be highly relevant to Alzheimer's disease and related dementias in which ion channel changes are implicated. The innovation and significance of this research is that our approach of computational modeling of membrane transport does not appear to have been applied to aid in the understanding of the biophysical basis of Alzheimer's disease. Computational models help to unify disparate data and can aid in in silico drug discovery efforts, which are urgently needed given the increasing percentage of the population that are at risk for neurodegenerative diseases.